Publications (40) View all
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Article: Tumor necrosis factor receptors and apoptosis of alveolar macrophages during early infection with attenuated and virulent Mycobacterium bovis.
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ABSTRACT: Apoptosis of macrophages has been reported as an effective host strategy to control the growth of intracellular pathogens, including pathogenic mycobacteria. Tumor necrosis factor-alpha (TNF-α) plays an important role in the modulation of apoptosis of infected macrophages. TNF-α exerts its biological activities via two distinct cell surface receptors, TNFR1 and TNFR2, whose extracellular domain can be released by proteolysis forming soluble TNF receptors (sTNFR-1 and sTNFR-2). The signaling through TNFR1 initiates the majority of the biological functions of TNF-α, leading to either cell death or survival whereas TNFR2 mediates primarily survival signals. Here, the expression of TNF-α receptors and the apoptosis of alveolar macrophages were investigated during the early phase of infection with attenuated and virulent mycobacteria in mice. A significant increase of apoptosis and high expression of TNFR1 were observed in alveolar macrophages at 3 and 7 days after infection with attenuated M. bovis but only on day 7 in infection with the virulent M. bovis. Low surface expression of TNFR1 and increased levels of sTNFR1 on day 3 after infection by the virulent strain were associated with reduced rates of apoptotic macrophages. In addition, a significant reduction in apoptosis of alveolar macrophages was observed in TNFR1(-/-) mice at day 3 after BCG infection. These results suggest a potential role for TNFR1 in mycobacteria induced alveolar macrophage apoptosis in vivo. In this scenario, shedding of TNFR1 seems to contribute to the modulation of macrophage apoptosis in a strain dependent manner. © 2013 The Authors. Immunology © 2013 Blackwell Publishing Ltd.Immunology 03/2013; · 3.32 Impact Factor -
Article: Anthraquinone derivative O,O'-bis-(3'-iodopropyl)-1,4-dihidroxyanthraquinone modulates immune response and improves experimental autoimmune encephalomyelitis.
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ABSTRACT: The present study investigated the effects of the anthraquinone derivative (O,O'-bis-(3'-iodopropyl)-1,4-dihidroxyanthraquinone - DIPDHAQ), mitoxantrone analog, in an experimental autoimmune encephalomyelitis (EAE) model. The results showed that DIPDHAQ treatment improved the clinical signs of the disease (n=10; vehicle: 3.8 ± 0.3; DIPDHAQ: 1.4 ± 0.9). The improvement was associated with a decrease of inflammatory cells, demyelination, IL-17, IFN-γ, IL-12p40, IL-6, TGF-β, CCL5 and CCL20 levels in the spinal cord. DIPDHAQ presented a low cytotoxicity when in vitro assays were performed. Therefore, the findings suggest a major role for DIPDHAQ in multiple sclerosis, disease characterized as an autoimmune inflammatory disorder against myelin proteins of the brain and spinal cord. The attenuation of inflammation and consequently improvement of clinical signs, involving a decrease of pro-inflammatory cytokines and the low cytotoxicity of DIPDHAQ, suggest that this compound could be used as an alternative treatment for autoimmune diseases in the central nervous system.International immunopharmacology 06/2012; 14(2):127-32. · 2.21 Impact Factor -
Article: Immunomodulatory effects and improved prognosis of experimental autoimmune encephalomyelitis after O-tetradecanoyl-genistein treatment.
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ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a murine autoimmune disease used to study multiple sclerosis (MS), a human inflammatory demyelinating disease of the central nervous system. Genistein, an isoflavonoid phytoestrogenic compound found in soy, is known to reverse clinical signs of EAE. Although genistein has some potential in clinical application, it has some disadvantages related to its chemical structure, such as rapid in vivo metabolism and a fast decline in serum after oral administration. The present work investigates the treatment of EAE by using 7-O-tetradecanoyl-genistein (TDG), a more lipophilic analog of genistein obtained by esterification. The clinical course of EAE was investigated in C57Bl/6 mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG)(35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37RA. After 14 days of MOG immunization, mice were treated with TDG for seven days. Numbers of IL-17-producing cells and Foxp3 by CD4(+) T cells and CTLA-4 expression by CD3(+) T cells from brain were determined by flow cytometry. Levels of IL-6, IFN-γ and IL-10 were evaluated by ELISA. Brain sections were stained by hematoxylin and eosin method. The data obtained indicate that TDG treatment ameliorates the clinical signs of EAE, which correlates with a decrease of IL-17-producing cells and an increase in Foxp3(+)CD4(+) cells in the brain. TDG is also shown to enhance IL-10 production and CTLA-4 expression and to reduce IFN-γ and IL-6. Altogether, these findings suggest an immunomodulatory therapeutic role for TDG in EAE and multiple sclerosis.International immunopharmacology 02/2012; 12(2):465-70. · 2.21 Impact Factor -
Article: Synthesis of lipophilic genistein derivatives and their regulation of IL-12 and TNF-α in activated J774A.1 cells.
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ABSTRACT: Genistein modulates inflammatory responses in part by reducing the production of the pro-inflammatory cytokines IL-12, TNF-α, and nitric oxide, by activated macrophages in response to lipopolysaccharide stimulus. Previous studies have shown that synthetic lipophilic genistein glycosides were significantly more active than hydrophilic glycosides. The aims of this study were to synthesize and to evaluate the effect of novel lipophilic genistein derivatives on IL-12, TNF-α, and nitric oxide production by J774A.1 cells. The results show that the modification of genistein enables the generation of non-cytotoxic compounds with increased IL-12 inhibition. However, these derivatives failed to inhibit TNF-α. The nitric oxide production was notably inhibited by the monoester (2, 3) and monoether (6, 7) compounds in a dose-dependent manner.Chemical Biology & Drug Design 12/2011; 79(3):347-52. · 2.28 Impact Factor -
Article: Splenectomy increases atherosclerotic lesions in apolipoprotein E deficient mice.
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ABSTRACT: Atherosclerosis is an inflammatory immune disease associated with lipid accumulation in the intima layer of arteries. The spleen plays an important immune function, but its influence in development of atherosclerosis remains unclear. Evaluation of the role of the spleen in atherosclerosis is justified due to the high frequency of total splenectomies. In this work, the effect of splenectomy on the development of atherosclerosis in apolipoprotein E (ApoE) deficient mice was investigated. ApoE deficient mice were divided into a sham-operated control group (CT) and a splenectomized group (SP). Thirty days after surgery, animals were fed a high fat western diet. After 8 wk, mice were euthanized and their blood, heart, and aorta were subjected to analysis. Atherosclerotic lesion areas in the aortic root were stained with hematoxylin-eosin and quantified by morphometry. The atherosclerotic lesions in the thoracic and abdominal portions of aorta were determined by assessing the percentage of the luminal surface area stained by Sudan IV. Total serum cholesterol and anti-oxidized LDL antibodies were measured. Levels of total serum cholesterol did not vary significantly after splenectomy. Anti-oxidized LDL IgG antibodies were similar between groups. However, compared with the control group, lesions in the aortic root were significantly larger in splenectomized mice (P<0.01). These data were confirmed by the increase of atherosclerotic area in the thoracic and abdominal portions of aorta in splenectomized mice. These data indicate that splenectomy increases atherosclerotic lesions in ApoE deficient mice fed an atherogenic diet, suggesting an atheroprotector role of the spleen.Journal of Surgical Research 09/2011; 171(2):e231-6. · 2.25 Impact Factor
